Biphenyl-carboxamide derivatives and their use as p38 kinase inhibitors

ABSTRACT

Compounds of formula (I) or pharmaceutically acceptable derivatives thereof, and their use as pharmaceuticals, particularly as p38 kinase inhibitors.

This application claims the benefit of §371 application ofPCT/EP2004/003769, filed 7 Apr 2004 which claims benefit of 60/249,877,filed Nov. 17, 2000, and claims benefit of 60/310,561, filed Aug. 7,2001.

This invention relates to novel compounds and their use aspharmaceuticals, particularly as p38 kinase inhibitors, for thetreatment of certain diseases and conditions.

We have now found a group of novel compounds that are inhibitors of p38kinase.

According to the invention there is provided a compound of formula (I):

wherein

R¹ is a phenyl group which may be optionally substituted;

R² is C₁₋₆alkyl substituted by one to three groups independentlyselected from OH, oxo, cyano, —S(O)_(p)R⁴, halogen, C₁₋₆alkoxy, —NR⁵R⁶,—CONR⁵R⁶, —NCOR⁵, —COOR⁵, —SO₂NR⁵R⁶, —NHSO₂R⁵ and —NHCONHR⁵;

R³ is the group —CO—NH—(CH₂)_(q)—R⁷ or —NH—CO—R⁸;

R⁴ is selected from hydrogen, C₁₋₆alkyl, heterocyclyl optionallysubstituted by C₁₋₄alkyl, and phenyl wherein the phenyl is optionallysubstituted by up to two groups independently selected from C₁₋₆alkoxy,C₁₋₆alkyl and halogen;

R⁵ and R⁶ are each independently selected from hydrogen and C₁₋₆alkyl;

when q is 0 to 2, R⁷ is selected from hydrogen, C₁₋₆alkyl,—C₃₋₇cycloalkyl, —CONHR⁹, phenyl optionally substituted by R¹¹ and/orR¹², heteroaryl optionally substituted by R¹¹ and/or R¹² andheterocyclyl optionally substituted by R¹¹ and/or R¹², and

when q is 2, R⁷ is additionally selected from C₁₋₆alkoxy, NHCOR⁹,NHCONHR⁹, NR⁹R¹⁰ and OH;

R⁸ is selected from hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy,—(CH₂)_(r)—C₃₋₇cycloalkyl, trifluoromethyl, —(CH₂)_(s)phenyl optionallysubstituted by R¹³ and/or R¹⁴, —(CH₂)_(s)heteroaryl optionallysubstituted by R¹³ and/or R¹⁴, —(CH₂)_(s)heterocyclyl optionallysubstituted by R¹³ and/or R¹⁴ and —(CH₂)_(s)fused bicyclyl optionallysubstituted by R¹³ and/or R¹⁴;

R⁹ is selected from hydrogen, C₁₋₆alkyl and phenyl wherein the phenylgroup is optionally substituted by up to two substituents selected fromC₁₋₆alkyl and halogen,

R¹⁰ is selected from hydrogen and C₁₋₆alkyl, or

R⁹ and R¹⁰, together with the nitrogen atom to which they are bound,form a five- to six-membered heterocyclic or heteroaryl ring optionallycontaining one additional heteroatom selected from oxygen, sulfur andnitrogen, wherein the ring may be substituted by up to two C₁₋₆alkylgroups;

R¹¹ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, —CONR¹⁰R¹⁵, —NHCOR¹⁵,—SO₂NHR¹⁵, —NHSO₂R¹⁵, halogen, trifluoromethyl, -Z-(CH₂)_(t)-phenyloptionally substituted by one or more halogen atoms,-Z-(CH₂)_(t)-heterocyclyl or -Z-(CH₂)_(t)-heteroaryl wherein theheterocyclyl or heteroaryl group is optionally substituted by one ormore substituents selected from C₁₋₆alkyl,

R¹² is selected from C₁₋₆alkyl and halogen, or

when R¹¹ and R¹² are adjacent to each other they may, together with thecarbon atoms to which they are bound, form a five- or six-memberedsaturated or unsaturated ring to give a fused bicyclic ring system,wherein the ring that is formed R¹¹ and R¹² optionally contains one ortwo heteroatoms selected from oxygen, nitrogen and sulfur;

R¹³ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(r)—C₃₋₇cycloalkyl,—CONR¹⁶R¹⁷, —NHCOR¹⁷, —SO₂NHR¹⁶, —NHSO₂R¹⁷, halogen, —(CH₂)_(k)NR¹⁸R¹⁹,oxy, trifluoromethyl, phenyl optionally substituted by one or more R¹⁴groups and heteroaryl wherein the heteroaryl is optionally substitutedby one or more R¹⁴ groups,

R¹⁴ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen, trifluoromethyl and—NR¹⁸R¹⁹, or

R¹³ and R¹⁴, together with the carbon atoms to which they are bound,form a five- or six-membered saturated or unsaturated ring to give afused bicyclic ring system, wherein the ring that is formed by R¹³ andR¹⁴ optionally contains one or two heteroatoms selected from oxygen,nitrogen and sulfur;

R¹⁵ is selected from hydrogen and C₁₋₆alkyl;

R¹⁶ is selected from hydrogen, C₁₋₆alkyl and phenyl wherein the phenylgroup is optionally substituted by one or more R¹⁴ groups,

R¹⁷ is selected from hydrogen and C₁₋₆alkyl, or

R¹⁶ and R¹⁷, together with the nitrogen atom to which they are bound,form a five- to six-membered heterocyclic ring optionally containing oneadditional heteroatom selected from oxygen, sulfur and N—R²⁰, whereinthe ring is optionally substituted by up to two C₁₋₆alkyl groups;

R¹⁸ is selected from hydrogen, C₁₋₆alkyl and —(CH₂)_(r)—C₃₋₇cycloalkyloptionally substituted by C₁₋₆alkyl,

R¹⁹ is selected from hydrogen and C₁₋₆alkyl, or

R¹⁸ and R¹⁹, together with the nitrogen atom to which they are bound,form a three- to seven-membered heterocyclic ring optionally containingone additional heteroatom selected from oxygen, sulfur and N—R²⁰,wherein the ring may contain up to one double bond and the ring isoptionally substituted by one or more R²¹ groups;

R²⁰ is selected from hydrogen and methyl;

R²¹ is selected from C₁₋₆alkyl, oxy, —CH₂OC₁₋₆alkyl, trichloromethyl and—N(C₁₋₆alkyl)₂;

U is selected from methyl and halogen;

W is selected from methyl and chlorine;

X and Y are each selected independently from hydrogen, methyl andhalogen;

Z is selected from —O— and a bond;

m is selected from 0, 1, 2, 3 and 4, and may be optionally substitutedwith up to two groups selected independently from C₁₋₆alkyl;

n, p, q, r and t are independently selected from 0, 1 and 2;

s is selected from 0 and 1; and

k is selected from 0, 1, 2 and 3;

or a pharmaceutically acceptable derivative thereof.

In a preferred embodiment, the molecular weight of a compound of formula(I) does not exceed 1000, more preferably 800, even more preferably 600.

The group R¹ may be optionally substituted by up to three substituents,more preferably one or two substituents, selected independently from thegroup consisting of halogen, C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₇cycloalkyl,trifluoromethyl, benzyloxy, hydroxy, cyano, hydroxyC₁₋₆alkyl,—(CH₂)_(h)CO(CH₂)_(i)NR²²R²³, —(CH₂)_(h)CO₂R²², —(CH₂)_(h)NR²²COR²³,—(CH₂)_(h)OCOR²², —(CH₂)_(h)OCONR²²R²³, —(CH₂)_(h)NR²²COOR²³,—(CH₂)_(h)COR²², —(CH₂)_(h)SO₂NR²²R²³, —(CH₂)_(h)NR²²SO₂R²³, —SO₂R²²,—(CH₂)_(h)NR²²R²³, —O(CH₂)_(p)NR²²R²³, —(CH₂)_(h)NR²²CO(CH₂)_(i)NR²²R²³,—(CH₂)_(h)CONR²²SO₂R²³, —(CH₂)_(h)SO₂NR²²COR²³ and phenyloxy optionallysubstituted by a group A; or R¹ may be optionally substituted by twoadjacent substituents which, together with the carbon atoms to whichthey are bound, form a five- or six-membered saturated or unsaturatedring to give a fused bicyclic ring system. The ring that is fused to thephenyl ring may optionally contain one or two heteroatoms selected fromoxygen, nitrogen and sulfur.

R²² and R²³ are independently selected from hydrogen; C₁₋₆alkyloptionally substituted by up to three, more preferably one or two,hydroxy groups; trihalomethyl; benzyl; —(CH₂)_(j)COH; —(CH₂)_(j)NR²⁴R²⁵;and phenyl optionally substituted by up to three groups selected fromC₁₋₆alkyl and C₁₋₆alkoxy.

R²⁴ and R²⁵ are independently selected from hydrogen and C₁₋₄alkyl.

Group A is selected from halogen, —SO₂NH₂, —SO₂-(4-methyl)piperazinyl,—NR²²COC₁₋₆alkyl and —NR²²SO₂C₁₋₆alkyl.

h is selected from 0, 1, 2 or 3.

i is selected from 0, 1, 2 and 3.

j is selected from 2 or 3.

The optional substituents on the group R¹, including when the phenylring is part of a fused bicyclic system, may be located on any positionon the phenyl ring. In a more preferred embodiment, when there is onesubstituent on the group R¹, that substituent is located on the meta- orpara-position relative to the amide linkage. When there are two optionalsubstituents on the group R¹, these substituents preferably occupy themeta- and para-positions relative to the amide linkage.

In one embodiment, the substituents for the group R¹ include halogen, inparticular fluorine or chlorine; C₁₋₄alkyl, in particular methyl;trifluoromethyl; C₁₋₄alkoxy, in particular methoxy; phenyloxy optionallysubstituted by the group A; benzyloxy; hydroxy; cyano; hydroxyC₁₋₄alkyl,in particular —CH₂OH or —CH₂CH₂OH; —(CH₂)_(h)— NHCH₃;—(CH₂)_(h)—N(CH₃)₂; —(CH₂)_(h)CONR²²R²³; —(CH₂)_(h)CO(CH₂)_(i)NR²²R²³,in particular —CONH₂ or —CH₂CONH₂; —(CH₂)_(h)—CO₂R²²;—(CH₂)_(h)NR²²COR²³; —(CH₂)_(h)OCOR²²; —(CH₂)_(h)OCONR²²R²³;—(CH₂)_(h)NR²²COOR²³; —(CH₂)_(h)COR²²; —(CH₂)_(h)SO₂NR²²R²³, inparticular —SO₂NH₂; —(CH₂)_(h)NR²²SO₂R²³, in particular —NHSO₂CH₃ or—CH₂NHSO₂CH₃; —SO₂R²², in particular —SO₂(CH₂)₂OH; —(CH₂)_(h)NR²²R²³, inparticular —CH₂N(CH₃)₂, —CH₂N(CH₃)(CH₂CH₃) or —NHCH(CH₂OH)₂;—(CH₂)_(h)NR²²CONR²²R²³; and —(CH₂)_(h)CONR²²SO₂R²³.

A representative example of R¹ is phenyl.

In one embodiment, R² is selected from C₁₋₄alkyl substituted by one ortwo OH groups, for example C₂₋₃alkyl substituted by one OH group.Representative examples of R² include —CH₂CH₂OH and —CH₂CH₂CH₂OH.

A representative example of R³ is —CO—NH—(CH₂)_(q)—R⁷.

In one embodiment, R⁴ is selected from hydrogen, C₁₋₄alkyl and phenyl.

In one embodiment, R⁵ and R⁶ are independently selected from hydrogenand C₁₋₄alkyl.

In one embodiment, R⁷ is selected from C₁₋₄alkyl, in particular ethyl orisopropyl; —C₃₋₇cycloalkyl, in particular cyclopropyl, cyclobutyl orcyclopentyl, especially cyclopropyl; phenyl optionally substituted byR¹¹ and/or R¹², in particular phenyl optionally substituted byC₁₋₄alkyl, C₁₋₄alkoxy, —CONH₂, —CONHCH₃, —NHCOCH₃, —SO₂NH₂, —NHSO₂CH₃,halogen, and/or -Z-(CH₂)_(t)heteroaryl wherein the heteroaryl ispreferably pyridyl, pyrimidyl or oxadiazolyl optionally substituted byC₁₋₄alkyl or phenyl optionally substituted with adjacent groups whichgive a fused bicyclic ring system, especially quinolinyl, isoquinolinylor tetralonyl; heteroaryl optionally substituted by R¹¹ and/or R¹², inparticular thienyl, pyridyl or benzofuran optionally substituted byC₁₋₄alkyl and/or —CONH₂; and NHCONHR⁹, in particular where R⁹ is phenyl.A representative example of R⁷ is cyclopropyl.

In one embodiment, R⁸ is selected from —(CH₂)_(s)phenyl optionallysubstituted by R¹³ and/or R¹⁴ and —(CH₂)_(s)heteroaryl optionallysubstituted by R¹³ and/or R¹⁴, especially furyl, thienyl, isoxazolyl orpyridyl optionally substituted by —(CH₂)_(k)NR¹⁸R¹⁹.

In one embodiment, R⁹ is selected from hydrogen, C₁₋₄alkyl and phenyloptionally substituted by C₁₋₄alkyl, in particular methyl.

In one embodiment, R¹⁰ is selected from hydrogen and C₁₋₄alkyl, inparticular hydrogen or methyl.

In one embodiment, R¹¹ is selected from C₁₋₄alkyl, in particular methyl;C₁₋₄alkoxy, in particular methoxy; —CONR¹⁰R¹⁵, in particular —CONHCH₃ orCONH₂; —NHCOR¹⁵, in particular —NHCOCH₃; —SO₂NHR¹⁵, in particular—SO₂NH₂; —NHSO₂R¹⁵, in particular —NHSO₂CH₃; halogen, in particularchlorine; and -Z-(CH₂)_(t)heteroaryl wherein the heteroaryl ispreferably pyridyl, pyrimidyl or oxadiazolyl optionally substituted byC₁₋₄alkyl.

In one embodiment, R¹² is selected from C₁₋₄alkyl, fluorine andchlorine, in particular, methyl or chlorine.

In one embodiment, R¹³ is selected from C₁₋₄alkyl, halogen, —NR¹⁸R¹⁹,C₃₋₆cycloalkyl, phenyl optionally substituted by one or more R¹⁴ groupsand heteroaryl optionally substituted by one or more R¹⁴ groups.

In one embodiment, R¹⁴ is selected from C₁₋₂alkyl, halogen and —NR¹⁸R¹⁹.

In one embodiment, R¹⁵ is selected from hydrogen and methyl.

In one embodiment, R¹⁶ is selected from hydrogen and C₁₋₄alkyl.

In one embodiment, R¹⁷ is selected from hydrogen and C₁₋₄alkyl.

In one embodiment, R¹⁸ is selected from hydrogen, C₁₋₄alkyl,C₃₋₆cycloalkyl and —CH₂C₃₋₆cycloalkyl.

In one embodiment, R¹⁹ is selected from hydrogen and C₁₋₄alkyl.

In another embodiment, R¹⁸ and R¹⁹, together with the nitrogen atom towhich they are bound, form a five to six membered heterocyclic ringoptionally containing up to one additional heteroatom selected fromoxygen, sulfur and N—R²⁰, wherein R²⁰ is methyl, and the ring may besubstituted by one or more R²¹ groups. In a further embodiment, R¹⁸ andR¹⁹, together with the nitrogen atom to which they are bound, form apyrrolidinyl group.

In one embodiment, R²⁰ is methyl.

In one embodiment, R²¹ is selected from methyl and oxy.

A representative example of W is methyl.

In one embodiment, X and Y are each selected independently fromhydrogen, chlorine and fluorine. In a further embodiment, X is fluorine.A representative example of X and Y is hydrogen.

In one embodiment, Z is a bond.

In one embodiment, m is selected from 0, 1 and 2. Representativeexamples of m include 0 and 1.

In one embodiment, n is selected from 0 and 1. A representative exampleof n is 0.

In one embodiment, p is selected from 0 and 2.

In one embodiment, q is selected from 0 and 1. A representative exampleof q is 0.

In one embodiment, r is 0.

In one embodiment, s is 0.

In one embodiment, t is selected from 0 and 1.

In one embodiment, k is selected from 0, 1 and 2.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described hereinabove.

Particular compounds according to the invention include those mentionedin the examples and their pharmaceutically derivatives.

As used herein, the term “pharmaceutically acceptable” means a compoundwhich is suitable for pharmaceutical use. Salts and solvates ofcompounds of the invention which are suitable for use in medicine arethose wherein the counterion or associated solvent is pharmaceuticallyacceptable. However, salts and solvates having non-pharmaceuticallyacceptable counterions or associated solvents are within the scope ofthe present invention, for example, for use as intermediates in thepreparation of other compounds of the invention and theirpharmaceutically acceptable salts and solvates.

As used herein, the term “pharmaceutically acceptable derivative”, meansany pharmaceutically acceptable salt, solvate or prodrug e.g. ester, ofa compound of the invention, which upon administration to the recipientis capable of providing (directly or indirectly) a compound of theinvention, or an active metabolite or residue thereof. Such derivativesare recognizable to those skilled in the art, without undueexperimentation. Nevertheless, reference is made to the teaching ofBurger's Medicinal Chemistry and Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent of teaching such derivatives. Preferred pharmaceuticallyacceptable derivatives are salts, solvates, esters, carbamates andphosphate esters. Particularly preferred pharmaceutically acceptablederivatives are salts, solvates and esters. Most preferredpharmaceutically acceptable derivatives are salts and esters.

The compounds of the present invention may be in the form of and/or maybe administered as a pharmaceutically acceptable salt. For a review onsuitable salts see Berge et al., J. Pharm. Sci., 1977, 66, 1-19.

Typically, a pharmaceutical acceptable salt may be readily prepared byusing a desired acid or base as appropriate. The salt may precipitatefrom solution and be collected by filtration or may be recovered byevaporation of the solvent.

Salts of the compounds of the present invention may, for example,comprise acid addition salts resulting from reaction of an acid with anitrogen atom present in a compound of formula (I). Salts encompassedwithin the term “pharmaceutically acceptable salts” refer to non-toxicsalts of the compounds of this invention. Suitable addition salts areformed from acids which form non-toxic salts and examples are acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate,citrate, dihydrochloride, edetate, edisylate, estolate, esylate,ethanesulphonate, formate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydrogen phosphate, hydroiodide, hydroxynaphthoate,iodide, isethionate, lactate, lactobionate, laurate, malate, maleate,mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine,oxalate, oxaloacetate, pamoate (embonate), palmitate, pantothenate,phosphate/diphosphate, piruvate, polygalacturonate, saccharate,salicylate, stearate, subacetate, succinate, sulphate, tannate,tartrate, teoclate, tosylate, triethiodide, trifluoroacetate andvalerate.

Pharmaceutically acceptable base salts include ammonium salts such as atrimethylammonium salt, alkali metal salts such as those of sodium andpotassium, alkaline earth metal salts such as those of calcium andmagnesium and salts with organic bases, including salts of primary,secondary and tertiary amines, such as isopropylamine, diethylamine,ethanolamine, trimethylamine, dicyclohexyl amine andN-methyl-D-glucamine.

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. As used herein, the term “solvate”refers to a complex of variable stoichiometry formed by a solute (inthis invention, a compound of formula (I) or a salt thereof) and asolvent. Such solvents for the purpose of the invention may notinterfere with the biological activity of the solute. Examples ofsuitable solvents include water, methanol, ethanol and acetic acid.Preferably the solvent used is a pharmaceutically acceptable solvent.Examples of suitable pharmaceutically acceptable solvents include water,ethanol and acetic acid. Most preferably the solvent used is water. Acomplex with water is known as a “hydrate”. Solvates of the compound ofthe invention are within the scope of the invention.

As used herein, the term “prodrug” means a compound which is convertedwithin the body, e.g. by hydrolysis in the blood, into its active formthat has medical effects. Pharmaceutically acceptable prodrugs aredescribed in T. Higuchi and V. Stella, Prodrugs as Novel DeliverySystems, Vol. 14 of the A.C.S. Symposium Series; Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987; and in D. Fleisher, S. Ramon andH. Barbra “Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs”, Advanced Drug Delivery Reviews (1996) 19(2)115-130, each of which are incorporated herein by reference.

Prodrugs are any covalently bonded carriers that release a compound offormula (I) in vivo when such prodrug is administered to a patient.Prodrugs are generally prepared by modifying functional groups in a waysuch that the modification is cleaved, either by routine manipulation orin vivo, yielding the parent compound. Prodrugs include, for example,compounds of this invention wherein hydroxy or amine groups are bondedto any group that, when administered to a patient, cleaves to form thehydroxy or amine groups. Thus, representative examples of prodrugsinclude (but are not limited to) acetate, formate and benzoatederivatives of alcohol and amine functional groups of the compounds offormula (I). Further, in the case of a carboxylic acid (—COOH), estersmay be employed, such as methyl esters, ethyl esters, and the like.Esters may be active in their own right and/or be hydrolysable under invivo conditions in the human body. Suitable pharmaceutically acceptablein vivo hydrolysable ester groups include those which break down readilyin the human body to leave the parent acid or its salt.

As used herein, the term “alkyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms. Forexample, C₁₋₆alkyl means a straight or branched alkyl containing atleast 1, and at most 6, carbon atoms. Examples of “alkyl” as used hereininclude, but are not limited to, methyl, ethyl, n-propyl, n-butyl,n-pentyl, isobutyl, isopropyl, t-butyl and hexyl. A C₁₋₄alkyl group ispreferred, for example methyl, ethyl or isopropyl. The said alkyl groupsmay be optionally substituted with one or more fluorine atoms, forexample, trifluoromethyl.

As used herein, the term “alkoxy” refers to straight or branched chainalkoxy groups containing the specified number of carbon atoms. Forexample, C₁₋₆alkoxy means a straight or branched alkoxy containing atleast 1, and at most 6, carbon atoms. Examples of “alkoxy” as usedherein include, but are not limited to, methoxy, ethoxy, propoxy,prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy,pentoxy and hexyloxy. A C₁₋₄alkoxy group is preferred, for examplemethoxy or ethoxy.

As used herein, the term “cycloalkyl” refers to a non-aromatichydrocarbon ring containing the specified number of carbon atoms. Forexample, C₃₋₇cycloalkyl means a non-aromatic ring containing at leastthree, and at most seven, ring carbon atoms. Examples of “cycloalkyl” asused herein include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. A C₃₋₅cycloalkyl group ispreferred, for example cyclopropyl.

As used herein, the terms “heteroaryl ring” and “heteroaryl” refer to amonocyclic five- to seven-membered unsaturated hydrocarbon ringcontaining at least one heteroatom selected from oxygen, nitrogen andsulfur. Preferably, the heteroaryl ring has five or six ring atoms.Examples of heteroaryl rings include, but are not limited to, furyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. Aparticularly preferred heteroaryl ring is pyridyl. The said ring may beoptionally substituted by one or more substituents independentlyselected from C₁₋₆alkyl and oxy. The terms “heteroaryl ring” and“heteroaryl” also refer to fused aromatic rings comprising at least oneheteroatom selected from oxygen, nitrogen and sulfur. Preferably, thefused ring each have five or six ring atoms. Examples of fused aromaticrings include, but are not limited to, indolyl, isoindolyl, azaindolyl,benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl,benzothiophenyl, quinolyl, isoquinolyl, quinazolinyl, cinnolinyl andphthalazinyl, in particular benzofuranyl.

As used herein, the terms “heterocyclic rings” and “heterocyclyl” referto a monocyclic three- to seven-membered saturated or non-aromatic,unsaturated hydrocarbon ring containing at least one heteroatom selectedfrom oxygen, nitrogen and sulfur. Preferably, the heterocyclyl ring hasfive or six ring atoms. Examples of heterocyclyl groups include, but arenot limited to, aziridinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidyl, piperazinyl,morpholino and thiomorpholino. The said ring may be optionallysubstituted by one or more substituents independently selected fromC₁₋₆alkyl and oxy.

As used herein, the term “fused bicyclic ring system” refers to a ringsystem comprising two five- to seven-membered saturated or unsaturatedhydrocarbon rings, the ring system optionally containing one or moreheteroatoms independently selected from oxygen, nitrogen and sulfur.Preferably, each ring has five or six ring atoms. Examples of suitablefused bicyclic rings include, but are not limited to, naphthyl, indolyl,indolinyl, benzothienyl, quinolyl, isoquinolyl, tetrahydroquinolyl,benzodioxanyl, indanyl and tetrahydronaphthyl. Each ring may beoptionally substituted with one or more substitutents selected fromhalogen, C₁₋₆alkyl, oxy, —(CH₂)_(h)NR²²R²³, —CO(CH₂)_(h)NR²²R²³ andimidazolyl. Particularly preferred substituents are chlorine, imidazolyland —CH₂—N(CH₃)₂.

As used herein, the terms “halogen” or “halo” refer to the elementsfluorine, chlorine, bromine and iodine. Preferred halogens are fluorine,chlorine and bromine. A particularly preferred halogen is fluorine.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

With regard to stereoisomers, the compounds of structure (I) may haveone or more asymmetric carbon atom and may occur as racemates, racemicmixtures and as individual enantiomers or diastereomers. All suchisomeric forms are included within the present invention, includingmixtures thereof.

Cis (E) and trans (Z) isomerism may also occur. The present inventionincludes the individual stereoisomers of the compound of the inventionand, where appropriate, the individual tautomeric forms thereof,together with mixtures thereof.

Separation of diastereoisomers or cis and trans isomers may be achievedby conventional techniques, e.g. by fractional crystallisation,chromatography or H.P.L.C. A stereoisomeric mixture of the agent mayalso be prepared from a corresponding optically pure intermediate or byresolution, such as H.P.L.C. of the corresponding racemate using asuitable chiral support or by fractional crystallisation of thediastereoisomeric salts formed by reaction of the corresponding racematewith a suitable optically active acid or base, as appropriate.

Furthermore, some of the crystalline forms of the compounds of structure(I) may exist as polymorphs, which are included in the presentinvention.

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention are prepared in the workingExamples.

For example, a general method (A) for preparing the compounds of Formula(I) comprises the reactions set out in Scheme 1 below.

For example, a general method (B) for preparing the compounds of Formula(I) comprises the reactions set out in Scheme 2 below.

For example, a general method (C) for preparing the compounds of Formula(I) comprises the reactions set out in Scheme 3 below.

For example, a general method (D) for preparing the compounds of Formula(I) comprises the reactions set out in Scheme 4 below.

For example, a general method (E) for preparing the compounds of Formula(I) comprises the reactions set out in Scheme 5 below.

For example, a general method (F) for preparing the compounds of Formula(I) wherein R⁸ is

comprises the reactions set out in Scheme 6 below.

For example, a general method (G) for preparing the compounds of Formula(I) comprises the reactions set out in Scheme 7 below.

Thus, according to the invention there is provided a process forpreparing a compound of formula (I) which comprises:

(a) reacting a compound of formula (XXII)

wherein R¹, R², U, W, X, Y, m and n are as defined above,with a compound of formula (XXIII)R⁷—(CH₂)_(q)—NH₂  (XXIII)wherein R⁷ and q are as defined above,under amide forming conditions (if desired, the acid compound (XXII) maybe converted to an activated form of the acid, for example the acidchloride, by treatment with, for example, oxalyl chloride, and then theactivated acid thus formed reacted with the amine compound (XXIII));(b) reacting a compound of formula (XXIV)

wherein R³, U, W, X, Y and n are as defined above,with a compound of formula (XXV)R¹(CH₂)_(m)NR²H  (XXV)wherein R¹, R² and m are as defined above,under amide forming conditions;(c) reacting a compound of formula (XXVI)

wherein R³, U, W, X, Y and n are as defined above,with a compound of formula (XXV) as defined above;(d) functional group conversion of a compound of formula (XXVII)

wherein R³, U, W, X, Y and n are as defined above and R^(1A) and R^(2A)are R¹ and R² as defined above or groups convertible to R¹ and R²,to give a compound of formula (I); or(e) reacting a compound of formula (XXVIII)

wherein R¹, R², U, W, X, Y, m and n are as defined above,with a compound of formula (XXIX)R⁸CO₂H  (XXIX)wherein R⁸ is as defined above,under amide forming conditions (if desired, the acid compound (XXIX) maybe converted to an activated form of the acid, for example the acidchloride, and then the activated acid thus formed reacted with the aminecompound (XXVIII)).

Suitable amide forming conditions are well known in the art and includetreating a solution of the acid, in for example THF, with an amine inthe presence of, for example, HOBT, HBTU and DIPEA.

Those skilled in the art will appreciate that in the preparation of thecompound of the invention or a solvate thereof it may be necessaryand/or desirable to protect one or more sensitive groups in the moleculeto prevent undesirable side reactions. Suitable protecting groups foruse according to the present invention are well known to those skilledin the art and may be used in a conventional manner. See, for example,“Protective groups in organic synthesis” by T. W. Greene and P. G. M.Wuts (John Wiley & sons 1991) or “Protecting Groups” by P. J. Kocienski(Georg Thieme Verlag 1994). Examples of suitable amino protecting groupsinclude acyl type protecting groups (e.g. formyl, trifluoroacetyl,acetyl), aromatic urethane type protecting groups (e.g.benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethaneprotecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc),t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl)and alkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl).Examples of suitable oxygen protecting groups may include for examplealkyl silyl groups, such as trimethylsilyl or tert-butyidimethylsilyl;alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such asacetate.

Whilst it is possible for the compounds of the present invention to beadministered as the raw chemical, the compounds of formula (I) and theirpharmaceutically acceptable derivatives are conveniently administered inthe form of pharmaceutical compositions eg when the agent is inadmixture with a suitable pharmaceutical excipient, diluent and/orcarrier selected with regard to the intended route of administration andstandard pharmaceutical practice.

Thus, in another aspect of the invention, we provide a pharmaceuticalcomposition comprising at least one compound of formula (I) or apharmaceutically acceptable derivative thereof, in association with oneor more pharmaceutically acceptable excipients, diluents and/orcarriers. The excipient, diluent or carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not deletrious to the recipient thereof.

According to a further aspect, the invention provides a pharmaceuticalcomposition comprising, as active ingredient, at least one compound ofthe invention or a pharmaceutically acceptable derivative thereof, inassociation one or more pharmaceutically acceptable excipients, diluentsand/or carriers for use in therapy, and in particular in the treatmentof human or animal subjects suffering from a condition susceptible toamelioration by an inhibitor of p38 kinase.

The present invention also provides a pharmaceutical compositioncomprising a therapeutically effective amount of the compounds of thepresent invention and a pharmaceutically acceptable excipient, diluentand/or carrier (including combinations thereof).

There is further provided by the present invention a process ofpreparing a pharmaceutical composition, which process comprises mixingat least one compound of the invention or a pharmaceutically acceptablederivative thereof, together with a pharmaceutically acceptableexcipient, diluent and/or carrier.

The pharmaceutical compositions may be for human or animal usage inhuman and veterinary medicine and will typically comprise any one ormore of a pharmaceutically acceptable excipient, diluent or carrier.Acceptable carriers or diluents for therapeutic use are well known inthe pharmaceutical art, and are described, for example, in Remington'sPharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).The choice of pharmaceutical excipient, diluent or carrier can beselected with regard to the intended route of administration andstandard pharmaceutical practice. The pharmaceutical compositions maycomprise as—or in addition to—the excipient, diluent or carrier anysuitable binder(s), lubricant(s), suspending agent(s), coating agent(s)and solubilising agent(s).

Preservatives, stabilisers, dyes and even flavouring agents may beprovided in the pharmaceutical composition. Examples of preservativesinclude sodium benzoate, sorbic acid and esters of p-hydroxybenzoicacid. Antioxidants and suspending agents may be also used.

For some embodiments, the agents of the present invention may also beused in combination with a cyclodextrin. Cyclodextrins are known to forminclusion and non-inclusion complexes with drug molecules. Formation ofa drug-cyclodextrin complex may modify the solubility, dissolution rate,bioavailability and/or stability property of a drug molecule.Drug-cyclodextrin complexes are generally useful for most dosage formsand administration routes. As an alternative to direct complexation withthe drug the cyclodextrin may be used as an auxiliary additive, e.g. asa carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrinsare most commonly used and suitable examples are described in WO91/11172, WO 94/02518 and WO 98/55148.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention may beprepared by processes known in the art, for example see WO 02/00196(SmithKline Beecham).

There may be different composition/formulation requirements dependent onthe different delivery systems. By way of example, the pharmaceuticalcomposition of the present invention may be formulated to be deliveredusing a mini-pump or by a mucosal route, for example, as a nasal sprayor aerosol for inhalation or ingestible solution, or parenterally inwhich the composition is formulated by an injectable form, for delivery,by, for example, an intravenous, intramuscular or subcutaneous route.Alternatively, the formulation may be designed to be delivered by bothroutes.

Where the agent is to be delivered mucosally through thegastrointestinal mucosa, it should be able to remain stable duringtransit though the gastrointestinal tract; for example, it should beresistant to proteolytic degradation, stable at acid pH and resistant tothe detergent effects of bile.

Where appropriate, the pharmaceutical compositions can be administeredby inhalation, in the form of a suppository or pessary, topically in theform of a lotion, solution, cream, ointment or dusting powder, by use ofa skin patch, orally in the form of tablets containing excipients suchas starch or lactose, or in capsules or ovules either alone or inadmixture with excipients, or in the form of elixirs, solutions orsuspensions containing flavouring or colouring agents, or they can beinjected parenterally, for example intravenously, intramuscularly orsubcutaneously. For parenteral administration, the compositions may bebest used in the form of a sterile aqueous solution which may containother substances, for example enough salts or monosaccharides to makethe solution isotonic with blood. For buccal or sublingualadministration the compositions may be administered in the form oftablets or lozenges which can be formulated in a conventional manner.

The routes for administration (delivery) include, but are not limitedto, one or more of: oral (e.g. as a tablet, capsule, or as an ingestiblesolution), topical, mucosal (e.g. as a nasal spray or aerosol forinhalation), nasal, parenteral (e.g. by an injectable form),gastrointestinal, intraspinal, intraperitoneal, intramuscular,intravenous, intrauterine, intraocular, intradermal, intracranial,intratracheal, intravaginal, intracerebroventricular, intracerebral,subcutaneous, ophthalmic (including intravitreal or intracameral),transdermal, rectal, buccal, epidural and sublingual. It is to beunderstood that not all of the compounds need be administered by thesame route. Likewise, if the composition comprises more than one activecomponent, then those components may be administered by differentroutes.

The compounds of formula (I) and their pharmaceutically acceptable saltsand solvates may be formulated for administration in any suitablemanner. They may, for example, be formulated for topical administrationor administration by inhalation or, more preferably, for oral,transdermal or parenteral administration. The pharmaceutical compositionmay be in a form such that it can effect controlled release of thecompounds of formula (I) and their pharmaceutically acceptablederivatives. In a preferred embodiment, the agents of the presentinvention are delivered systemically such as orally, buccally orsublingually. A particularly preferred method of administration, andcorresponding formulation, is oral administration.

For oral administration, the pharmaceutical composition may take theform of, and be administered as, for example, tablets (includingsub-lingual tablets) and capsules (each including timed release andsustained release formulations), ovules, pills, powders, granules,elixirs, tinctures, emulsions, solutions, syrups or suspensions preparedby conventional means with acceptable excipients for immediate-,delayed-, modified-, sustained-, pulsed- or controlled-releaseapplications.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. The tablets may also contain excipientssuch as microcrystalline cellulose, lactose, sodium citrate, calciumcarbonate, dibasic calcium phosphate and glycine, disintegrants such asstarch (preferably corn, potato or tapioca starch), sodium starchglycollate, croscarmellose sodium and certain complex silicates, andgranulation binders such as polyvinylpyrrolidone,hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),sucrose, gelatin and acacia. Additionally, lubricating agents such asmagnesium stearate, stearic acid, glyceryl behenate and talc may beincluded.

Solid compositions of a similar type may also be employed as fillers ingelatin capsules. Preferred excipients in this regard include lactose,starch, a cellulose, milk sugar or high molecular weight polyethyleneglycols. For aqueous suspensions and/or elixirs, the agent may becombined with various sweetening or flavouring agents, colouring matteror dyes, with emulsifying and/or suspending agents and with diluentssuch as water, ethanol, propylene glycol and glycerin, and combinationsthereof.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate, as, for example, starch or mannitol. Flavoring,preservative, dispersing and coloring agent can also be present.

Capsules can be made by preparing a powder mixture as described above,and filling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additives suchas peppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

The compounds of the present invention can also be administered in theform of liposome emulsion delivery systems, such as small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

The present invention includes pharmaceutical compositions containing0.1 to 99.5%, more particularly, 0.5 to 90% of a compound of the formula(I) in combination with a pharmaceutically acceptable carrier.

Likewise, the composition may also be administered in nasal, ophthalmic,optic, rectal, topical, intravenous (both bolus and infusion),intraperitoneal, intraarticular, subcutaneous or intramuscular,inhalation or insufflation form, all using forms well known to those ofordinary skill in the pharmaceutical arts.

For transdermal administration, the pharmaceutical composition may begiven in the form of a transdermal patch, such as a transdermaliontophoretic patch.

If the compound of the present invention is administered parenterally,then examples of such administration include one or more of:intravenously, intraarterially, intraperitoneally, intrathecally,intraventricularly, intraurethrally, intrasternally, intracranially,intramuscularly or subcutaneously administering the agent; and/or byusing infusion techniques. For parenteral administration, thepharmaceutical composition may be given as an injection or a continuousinfusion (e.g. intravenously, intravascularly or subcutaneously). Thecompositions may take such forms as suspensions, solutions or emulsionsin oily or aqueous vehicles and may contain formulatory agents such assuspending, stabilizing and/or dispersing agents. For administration byinjection these may take the form of a unit dose presentation or as amultidose presentation preferably with an added preservative.Alternatively for parenteral administration the active ingredient may bein powder form for reconstitution with a suitable vehicle. Forparenteral administration, the compound is best used in the form of asterile aqueous solution which may contain other substances, forexample, enough salts or glucose to make the solution isotonic withblood. The aqueous solutions should be suitably buffered (preferably toa pH of from 3 to 9), if necessary. The preparation of suitableparenteral formulations under sterile conditions is readily accomplishedby standard pharmaceutical techniques well-known to those skilled in theart.

The compositions of the present invention may be administered by directinjection.

The compounds of the invention may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

Alternatively the composition may be formulated for topical application,for example in the form of ointments, creams, lotions, eye ointments,eye drops, ear drops, mouthwash, impregnated dressings and sutures andaerosols, and may contain appropriate conventional additives, including,for example, preservatives, solvents to assist drug penetration, andemollients in ointments and creams. Such topical formulations may alsocontain compatible conventional carriers, for example cream or ointmentbases, and ethanol or oleyl alcohol for lotions. Such carriers mayconstitute from about 1% to about 98% by weight of the formulation; moreusually they will constitute up to about 80% by weight of theformulation.

For application topically to the skin, the agent of the presentinvention can be formulated as a suitable ointment containing the activecompound suspended or dissolved in, for example, a mixture with one ormore of the following: mineral oil, liquid petrolatum, white petrolatum,propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifyingwax and water.

Alternatively, it can be formulated as a suitable lotion or cream,suspended or dissolved in, for example, a mixture of one or more of thefollowing: mineral oil, sorbitan monostearate, a polyethylene glycol,liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkanesuch as tetrafluoroethane or heptafluoropropane, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol the dosage unit maybe determined by providing a valve to deliver a metered amount. Capsulesand cartridges of e.g. gelatin for use in an inhaler or insufflator maybe formulated containing a powder mix of a compound of the invention anda suitable powder base such as lactose or starch.

Alternatively, the compound of the present invention can be administeredin the form of a suppository or pessary, or it may be applied topicallyin the form of a gel, hydrogel, lotion, solution, cream, ointment ordusting powder.

The compounds of the present invention may also be administered by thepulmonary or rectal routes. They may also be administered by the ocularroute. For ophthalmic use, the compounds can be formulated as micronisedsuspensions in isotonic, pH adjusted, sterile saline, or, preferably, assolutions in isotonic, pH adjusted, sterile saline, optionally incombination with a preservative such as a benzylalkonium chloride.Alternatively, they may be formulated in an ointment such as petrolatum.

The pharmaceutical compositions generally are administered in an amounteffective for treatment or prophylaxis of a specific condition orconditions. Initial dosing in humans is accompanied by clinicalmonitoring of symptoms, such symptoms for the selected condition. Ingeneral, the compositions are administered in an amount of active agentof at least about 100 μg/kg body weight. In most cases they will beadministered in one or more doses in an amount not in excess of about 20mg/kg body weight per day. Preferably, in most cases, dose is from about100 μg/kg to about 5 mg/kg body weight, daily. For administrationparticularly to mammals, and particularly humans, it is expected thatthe daily dosage level of the active agent will be from 0.1 mg/kg to 10mg/kg and typically around 1 mg/kg. It will be appreciated that optimumdosage will be determined by standard methods for each treatmentmodality and indication, taking into account the indication, itsseverity, route of administration, complicating conditions and the like.The physician in any event will determine the actual dosage which willbe most suitable for an individual and will vary with the activity ofthe specific compound to be employed, the metabolic stability and lengthof action of that compound, age, weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination,severity of the particular condition and response of the particularindividual. The effectiveness of a selected actual dose can readily bedetermined, for example, by measuring clinical symptoms or standardanti-inflammatory indicia after administration of the selected dose. Theabove dosages are exemplary of the average case. There can, of course,be individual instances where higher or lower dosage ranges are merited,and such are within the scope of this invention. For conditions ordisease states as are treated by the present invention, maintainingconsistent daily levels in a subject over an extended period of time,e.g., in a maintenance regime, can be particularly beneficial. For oraland parenteral administration to humans, the daily dosage level of theagent may be in single or divided doses.

In another aspect, the present invention provides a compound of formula(I) or a pharmaceutically acceptable derivative thereof, for use intherapy.

The compounds of the present invention are generally inhibitors of theserine/threonine kinase p38 and are therefore also inhibitors ofcytokine production which is mediated by p38 kinase. Within the meaningof the term “inhibitors of the serine/threonine kinase p38” are includedthose compounds that interfere with the ability of p38 to transfer aphosphate group from ATP to a protein substrate according to the assaydescribed below.

It will be appreciated that the compounds of the invention may beselective for one or more of the isoforms of p38, for example p38α,p38β, p38γ and/or p38δ. In one embodiment, the compounds of theinvention selectively inhibit the p38α isoform. In another embodiment,the compounds of the invention selectively inhibit the p38β form. In afurther embodiment, the compounds of the invention selectively inhibitthe p38α and p38β isoforms. Assays for determining the selectivity ofcompounds for the p38 isoforms are described in, for example, WO99/61426, WO 00/71535 and WO 02/46158.

It is known that p38 kinase activity can be elevated (locally orthroughout the body), p38 kinase can be incorrectly temporally active orexpressed, p38 kinase can be expressed or active In an inappropriatelocation, p38 kinase can be constitutively expressed, or p38 kinaseexpression can be erratic; similarly, cytokine production mediated byp38 kinase activity can be occurring at inappropriate times,inappropriate locations, or it can occur at detrimentally high levels.

Accordingly, the present invention provides a method for the treatmentof a condition or disease state mediated by p38 kinase activity, ormediated by cytokines produced by the activity of p38 kinase, in asubject which comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof. The compound may be administered as asingle or polymorphic crystalline form or forms, an amorphous form, asingle enantiomer, a racemic mixture, a single stereoisomer, a mixtureof stereoisomers, a single diastereoisomer or a mixture ofdiastereoisomers.

The present invention also provides a method of inhibiting cytokineproduction which is mediated by p38 kinase activity in a subject, e.g. ahuman, which comprises administering to said subject in need of cytokineproduction inhibition a therapeutic, or cytokine-inhibiting, amount of acompound of the present invention. The compound may be administered as asingle or polymorphic crystalline form or forms, an amorphous form, asingle enantiomer, a racemic mixture, a single stereoisomer, a mixtureof stereoisomers, a single diastereoisomer or a mixture ofdiastereoisomers.

The present invention treats these conditions by providing atherapeutically effective amount of a compound of this invention. By“therapeutically effective amount” is meant a symptom-alleviating orsymptom-reducing amount, a cytokine-reducing amount, acytokine-inhibiting amount, a kinase-regulating amount and/or akinase-inhibiting amount of a compound. Such amounts can be readilydetermined by standard methods, such as by measuring cytokine levels orobserving alleviation of clinical symptoms. For example, the cliniciancan monitor accepted measurement scores for anti-inflammatorytreatments. It will be appreciated that reference to treatment includesacute treatment or prophylaxis as well as the alleviation of establishedsymptoms.

The compounds of the present invention can be administered to anysubject in need of inhibition or regulation of p38 kinase or in need ofinhibition or regulation of p38 mediated cytokine production. Inparticular, the compounds may be administered to mammals. Such mammalscan include, for example, horses, cows, sheep, pigs, mice, dogs, cats,primates such as chimpanzees, gorillas, rhesus monkeys, and, mostpreferably, humans.

Thus, the present invention provides methods of treating or reducingsymptoms in a human or animal subject suffering from, for example,rheumatoid arthritis, osteoarthritis, asthma, psoriasis, eczema,allergic rhinitis, allergic conjunctivitis, adult respiratory distresssyndrome, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, silicosis, endotoxemia, toxic shocksyndrome, inflammatory bowel disease, tuberculosis, atherosclerosis,neurodegenerative disease, Alzheimer's disease, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis, epilepsy, multiplesclerosis, aneurism, stroke, irritable bowel syndrome, muscledegeneration, bone resorption diseases, osteoporosis, diabetes,reperfusion injury, graft vs. host reaction, allograft rejections,sepsis, systemic cachexia, cachexia secondary to infection ormalignancy, cachexia secondary to acquired immune deficiency syndrome(AIDS), malaria, leprosy, infectious arthritis, leishmaniasis, Lymedisease, glomerulonephritis, gout, psoriatic arthritis, Reiter'ssyndrome, traumatic arthritis, rubella arthritis, Crohn's disease,ulcerative colitis, acute synovitis, gouty arthritis, spondylitis, andnon articular inflammatory conditions, for example,herniated/ruptured/prolapsed intervertebral disk syndrome, bursitis,tendonitis, tenosynovitis, fibromyalgic syndrome and other inflammatoryconditions associated with ligamentous sprain and regionalmusculoskeletal strain, pain, for example that associated withinflammation and/or trauma, osteopetrosis, restenosis, thrombosis,angiogenesis, cancer including breast cancer, colon cancer, lung canceror prostatic cancer, which comprises administering to said subject atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable derivative thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis, asthma,psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, systemic cachexia, glomerulonephritis,Crohn's disease, neurodegenerative disease, Alzheimer's disease,Parkinson's disease, epilepsy and cancer including breast cancer, coloncancer, lung cancer and prostatic cancer, which comprises administeringto said subject a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable derivative thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis, asthma,psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, systemic cachexia, glomerulonephritis,Crohn's disease and cancer including breast cancer, colon cancer, lungcancer and prostatic cancer, which comprises administering to saidsubject a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable derivative thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis, asthma,chronic pulmonary inflammation, chronic obstructive pulmonary disease,neurodegenerative disease, Alzheimer's disease, Parkinson's disease andepilepsy which comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from any type of pain includingchronic pain, rapid onset of analgesis, neuromuscular pain, headache,cancer pain, acute and chronic inflammatory pain associated withosteoarthritis and rheumatoid arthritis, post operative inflammatorypain, neuropathic pain, diabetic neuropathy, trigeminal neuralgia,post-hepatic neuralgia, inflammatory neuropathies and migraine painwhich comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof.

A further aspect of the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable derivative thereof, in themanufacture of a medicament for use in the treatment of a condition ordisease state mediated by p38 kinase activity or mediated by cytokinesproduced by p38 kinase activity.

The compounds of formula (I) and their derivatives may be employed aloneor in combination with other therapeutic agents for the treatment of theabove-mentioned conditions. The invention thus provides, in a furtheraspect, a combination comprising a compound of the invention or apharmaceutically acceptable derivative thereof together with a furthertherapeutic agent.

In particular, in rheumatoid arthritis therapy, combination with otherchemotherapeutic or antibody agents is envisaged. Combination therapiesaccording to the present invention thus comprise the administration ofat least one compound of formula (I) or a pharmaceutically acceptablesalt or solvate thereof and at least one other pharmaceutically activeagent. The compound(s) of formula (I) or pharmaceutically acceptablesalt(s) or solvate(s) thereof and the other pharmaceutically activeagent(s) may be administered together or separately and, whenadministered separately, this may occur separately or sequentially inany order. The amounts of the compound(s) of formula (I) orpharmaceutically acceptable salt(s) or solvate(s) thereof and the otherpharmaceutically active agent(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect. Appropriate doses will be readily appreciated bythose skilled in the art. It will be appreciated that the amount of acompound of the invention required for treatment will vary with thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or veterinarian. Examples of other pharmaceutically activeagents which may be employed in combination with compounds of formula(I) and their salts and solvates for rheumatoid arthritis therapyinclude: immunosuppresants such as amtolmetin guacil, mizoribine andrimexolone; anti-TNFα agents such as etanercept, infliximab, diacerein;tyrosine kinase inhibitors such as leflunomide; kallikrein antagonistssuch as subreum; interleukin 11 agonists such as oprelvekin; interferonbeta 1 agonists; hyaluronic acid agonists such as NRD-101 (Aventis);interleukin 1 receptor antagonists such as anakinra; CD8 antagonistssuch as amiprilose hydrochloride; beta amyloid precursor proteinantagonists such as reumacon; matrix metalloprotease inhibitors such ascipemastat and other disease modifying anti-rheumatic drugs (DMARDs)such as methotrexate, sulphasalazine, cyclosporin A, hydroxychoroquine,auranofin, aurothioglucose, gold sodium thiomalate and penicillamine.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier or excipient comprise a furtheraspect of the invention.

The individual components of such combinations may be administeredeither sequentially or simultaneously in separate or combinedpharmaceutical formulations by any convenient route.

When administration is sequential, either the compound of the inventionor the second therapeutic agent may be administered first. Whenadministration is simultaneous, the combination may be administeredeither in the same or different pharmaceutical composition.

When combined in the same formulation it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the formulation. When formulated separately they maybe provided in any convenient formulation, conveniently in such manneras are known for such compounds in the art.

EXAMPLES

The following examples are illustrative embodiments of the invention,not limiting the scope of the invention in any way. Reagents arecommercially available or are prepared according to procedures in theliterature.

LCMS was conducted on a column (3.3 cm×4.6 mm ID, 3 um ABZ+PLUS), at aFlow Rate of 3 ml/min, Injection Volume of 5 μl, at room temperature andUV Detection Range at 215 to 330 nm.

General Method

A solution of the acid (50 mg) in DMF (1 ml) was treated with HATU (65mg) at room temperature. After 5 minutes this was added to a solution ofthe amine (0.17 mmol) and HOBt (23 mg) in DMF (1 ml). DIPEA (87 μl) wasadded. The reaction mixtures were left at room temperature for 16 hrs,then concentrated in vacuo. The residues were dissolved in DCM (1 ml)and each was loaded onto a 1 gm aminopropyl SPE cartridge that had beenpre-equilibrated with DCM. Residual sample was washed on with anotherportion of DCM (0.5 ml), the cartridge was then eluted with DCM (2.5ml), chloroform (2.5 ml), ethyl acetate (2.5 ml), MeOH (2.5 ml). Thefractions containing product were isolated by evaporation.

Retention Example Amine Time (mins) MH+ Example 1 2-(benzylamino)ethanol2.97 429 N^(4′)-benzyl-N³-cyclopropyl-N^(4′)- (2-hydroxyethyl)-6-methyl-1,1′-biphenyl-3,4′- dicarboxamide

Example 2 3-(benzylamino)-1- 2.99 443N^(4′)-benzyl-N³-cyclopropyl-N^(4′)- propanol(3-hydroxypropyl)-6-methyl- 1,1′-biphenyl-3,4′- dicarboxamide

Example 3 2-(phenylamino)ethanol 3.61 415 N³-cyclopropyl-N^(4′)-(2-hydroxyethyl)-6-methyl-N^(4′)- phenyl-1,1′-biphenyl-3,4′- dicarboxamide

Abbreviations

-   DCM Dichloromethane-   DIPEA N,N-Diisopropylethylamine-   DMF Dimethylformamide-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBT 1-Hydroxybenzotriazole hydrate-   SPE Solid phase extraction

BIOLOGICAL EXAMPLES

The activity of compounds of formula (I) as p38 inhibitors may bedetermined by the following in vitro assays:

Fluorescence Anisotropy Kinase Binding Assay

The kinase enzyme, fluorescent ligand and a variable concentration oftest compound are incubated together to reach thermodynamic equilibriumunder conditions such that in the absence of test compound thefluorescent ligand is significantly (>50%) enzyme bound and in thepresence of a sufficient concentration (>10×K_(i)) of a potent inhibitorthe anisotropy of the unbound fluorescent ligand is measurably differentfrom the bound value.

The concentration of kinase enzyme should preferably be ≧1×K_(f). Theconcentration of fluorescent ligand required will depend on theinstrumentation used, and the fluorescent and physicochemicalproperties. The concentration used must be lower than the concentrationof kinase enzyme, and preferably less than half the kinase enzymeconcentration. A typical protocol is:

All components dissolved in Buffer of final composition 62.5 mM HEPES,pH 7.5, 1.25 mM CHAPS, 1.25 mM DTT, 12.5 mM MgCl₂ 3.3% DMSO.

-   -   p38 Enzyme concentration: 12 nM    -   Fluorescent ligand concentration: 5 nM    -   Test compound concentration: 0.1 nM-100 uM    -   Components incubated in 30 ul final volume in NUNC 384 well        black microtitre plate until equilibrium reached (5-30 mins)    -   Fluorescence anisotropy read in LJL Acquest.        Definitions:    -   K_(i)=dissociation constant for inhibitor binding    -   K_(f)=dissociation constant for fluorescent ligand binding    -   The fluorescent ligand is the following compound:

which is derived from5-[2-(4-aminomethylphenyl)-5-pyridin-4-yl-1H-imidazolyl]-2-chlorophenoland rhodamine green.Results

The compounds described in the Examples were tested as described aboveand had IC₅₀ values of <10 μM.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process or use claims and may include, by way ofexample and without limitation, one or more of the following claim:

1. A compound of formula (I):

wherein R¹ is a phenyl group which may be optionally substituted; R² isC₁₋₆alkyl substituted by one to three groups independently selected fromOH, oxo, cyano, —S(O)_(p)R⁴, halogen, C₁₋₆alkoxy, —NR⁵R⁶, —CONR⁵R⁶,—NCOR⁵, —COOR⁵, —SO₂NR⁵R⁶, —NHSO₂R⁵ and —NHCONHR⁵; R³ is the group—CO—NH—(CH₂)_(q)—R⁷ or —NH—CO—R⁸; R⁴ is selected from hydrogen,C₁₋₆alkyl, heterocyclyl optionally substituted by C₁₋₄alkyl, and phenylwherein the phenyl is optionally substituted by up to two groupsindependently selected from C₁₋₆alkoxy, C₁₋₆alkyl and halogen; R⁵ and R⁶are each independently selected from hydrogen and C₁₋₆alkyl; when q is 0to 2, R⁷ is selected from hydrogen, C₁₋₆alkyl, —C₃₋₇cycloalkyl, —CONHR⁹,phenyl optionally substituted by R¹¹ and/or R¹², heteroaryl optionallysubstituted by R¹¹ and/or R¹² and heterocyclyl optionally substituted byR¹¹ and/or R¹², and when q is 2, R⁷ is additionally selected fromC₁₋₆alkoxy, NHCOR⁹, NHCONHR⁹, NR⁹R¹⁰ and OH; R⁸ is selected fromhydrogen, C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(r)—C₃₋₇cycloalkyl,trifluoromethyl, —(CH₂)_(s)phenyl optionally substituted by R¹³ and/orR¹⁴, —(CH₂)_(s)heteroaryl optionally substituted by R¹³ and/or R¹⁴,—(CH₂)_(s)heterocyclyl optionally substituted by R¹³ and/or R¹⁴ and—(CH₂)_(s)fused bicyclyl optionally substituted by R¹³ and/or R¹⁴; R⁹ isselected from hydrogen, C₁₋₆alkyl and phenyl wherein the phenyl group isoptionally substituted by up to two substituents selected from C₁₋₆alkyland halogen, R¹⁰ is selected from hydrogen and C₁₋₆alkyl, or R⁹ and R¹⁰,together with the nitrogen atom to which they are bound, form a five- tosix-membered heterocyclic or heteroaryl ring optionally containing oneadditional heteroatom selected from oxygen, sulfur and nitrogen, whereinthe ring may be substituted by up to two C₁₋₆alkyl groups; R¹¹ isselected from C₁₋₆alkyl, C₁₋₆alkoxy, —CONR¹⁰R¹⁵, —NHCOR¹⁵, —SO₂NHR¹⁵,—NHSO₂R¹⁵, halogen, trifluoromethyl, —Z—(CH₂)_(t)-phenyl optionallysubstituted by one or more halogen atoms, —Z—(CH₂)_(t)-heterocyclyl or—Z—(CH₂)_(t)-heteroaryl wherein the heterocyclyl or heteroaryl group isoptionally substituted by one or more substituents selected fromC₁₋₆alkyl, R¹² is selected from C₁₋₆alkyl and halogen, or when R¹¹ andR¹² are adjacent to each other they may, together with the carbon atomsto which they are bound, form a five- or six-membered saturated orunsaturated ring to give a fused bicyclic ring system, wherein the ringthat is formed R¹¹ and R¹² optionally contains one or two heteroatomsselected from oxygen, nitrogen and sulfur; R¹³ is selected fromC₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(r)—C₃₋₇cycloalkyl, —CONR¹⁶R¹⁷, —NHCOR¹⁷,—SO₂NHR¹⁶, —NHSO₂R¹⁷, halogen, —(CH₂)_(k)NR¹⁸R¹⁹, oxy, trifluoromethyl,phenyl optionally substituted by one or more R¹⁴ groups and heteroarylwherein the heteroaryl is optionally substituted by one or more R¹⁴groups, R¹⁴ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen,trifluoromethyl and —NR¹⁸R¹⁹, or R¹³ and R¹⁴, together with the carbonatoms to which they are bound, form a five- or six-membered saturated orunsaturated ring to give a fused bicyclic ring system, wherein the ringthat is formed by R¹³ and R¹⁴ optionally contains one or two heteroatomsselected from oxygen, nitrogen and sulfur; R¹⁵ is selected from hydrogenand C₁₋₆alkyl; R¹⁶ is selected from hydrogen, C₁₋₆alkyl and phenylwherein the phenyl group is optionally substituted by one or more R¹⁴groups, R¹⁷ is selected from hydrogen and C₁₋₆alkyl, or R¹⁶ and R¹⁷,together with the nitrogen atom to which they are bound, form a five- tosix-membered heterocyclic ring optionally containing one additionalheteroatom selected from oxygen, sulfur and N—R²⁰, wherein the ring isoptionally substituted by up to two C₁₋₆alkyl groups; R¹⁸ is selectedfrom hydrogen, C₁₋₆alkyl and —(CH₂)_(r)—C₃₋₇cycloalkyl optionallysubstituted by C₁₋₆alkyl, R¹⁹ is selected from hydrogen and C₁₋₆alkyl,or R¹⁸ and R¹⁹, together with the nitrogen atom to which they are bound,form a three- to seven-membered heterocyclic ring optionally containingone additional heteroatom selected from oxygen, sulfur and N—R²⁰,wherein the ring may contain up to one double bond and the ring isoptionally substituted by one or more R²¹ groups; R²⁰ is selected fromhydrogen and methyl; R²¹ is selected from C₁₋₆alkyl, oxy,—CH₂OC₁₋₆alkyl, trichloromethyl and —N(C₁₋₆alkyl)₂; U is selected frommethyl and halogen; W is selected from methyl and chlorine; X and Y areeach selected independently from hydrogen, methyl and halogen; Z isselected from —O— and a bond; m is selected from 0, 1, 2, 3 and 4, andmay be optionally substituted with up to two groups selectedindependently from C₁₋₆alkyl; n, p, q, r and t are independentlyselected from 0, 1 and 2; s is selected from 0 and 1; and k is selectedfrom 0, 1, 2 and 3; or a pharmaceutically acceptable salt thereof.
 2. Acompound according to claim 1 wherein R¹ is phenyl.
 3. A compoundaccording to claim 1 wherein R² is C₁₋₄alkyl substituted by one or twoOH groups.
 4. A compound according to claim 1 wherein m is 0 or
 1. 5. Acompound according to claim 1 wherein R⁴ is —C₃₋₇cycloalkyl.
 6. Acompound according to claim 1 which isN^(4′)-benzyl-N³-cyclopropyl-N^(4′)-(2-hydroxyethyl)-6-methyl-1,1′-biphenyl-3,4′-dicarboxamide;N^(4′)-benzyl-N³-cyclopropyl-N^(4′)-(3-hydroxypropyl)-6-methyl-1,1′-biphenyl-3,4′-dicarboxamide;N³-cyclopropyl-N^(4′)-(2-hydroxyethyl)-6-methyl-N^(4′)-phenyl-1,1′-biphenyl-3,4′-dicarboxamide;or a pharmaceutically acceptable salt thereof.
 7. A process forpreparing a compound according to claim 1 which comprises: (a) reactinga compound of formula (XXII)

wherein R¹, R², U, W, X, Y, m and n are as defined in claim 1, with acompound of formula (XXIII)R⁷—(CH₂)_(q)—NH₂  (XXIII) wherein R⁷ and q are as defined in claim 1,under amide forming conditions, optionally converting the acid compound(XXII) to an activated form of the acid before reaction with the aminecompound (XXIII); (b) reacting a compound of formula (XXIV)

wherein R³, U, W, X, Y and n are as defined in claim 1, with a compoundof formula (XXV)R¹(CH₂)_(m)NR²H  (XXV) wherein R¹, R² and m are as defined in claim 1,under amide forming conditions; (c) reacting a compound of formula(XXVI)

wherein R³, U, W, X, Y and n are as defined in claim 1, with a compoundof formula (XXV) as defined above; (d) functional group conversion of acompound of formula (XXVII)

wherein R³, U, W, X, Y and n are as defined in claim 1 and R^(1A) andR^(2A) are R¹ and R² as defined in claim 1 or groups convertible to R¹and R², to give a compound of formula (I); or (e) reacting a compound offormula (XXVIII)

wherein R¹, R², U, W, X, Y, m and n are as defined in claim 1, with acompound of formula (XXIX)R⁸CO₂H  (XXIX) wherein R⁸ is as defined in claim 1, under amide formingconditions, optionally converting the acid compound (XXIX) to anactivated form of the acid before reaction with the amine compound(XXVIII).
 8. A pharmaceutical composition comprising at least onecompound according to claim 1 or a pharmaceutically salt thereof, inassociation with one or more pharmaceutically acceptable excipients,diluents and/or carriers.
 9. A method for treating a condition ordisease state mediated by p38 kinase activity or mediated by cytokinesproduced by the activity of p38 kinase comprising administering to apatient in need thereof a compound according to claim 1 or apharmaceutically acceptable salt thereof.
 10. A compound according toclaim 1 wherein R¹ is a phenyl substituted up to three times by halogen;C₁₋₄alkyl; C₁₋₄alkoxy; phenyloxy optionally substituted by the group A;benzyloxy; hydroxy; cyano; hydroxyC₁₋₄alkyl; —(CH²)h—NHCH³;—(CH₂)_(h)—N(CH₃)₂; —(CH₂)_(h)CONR²²R²³; —(CH₂)_(h)CO(CH₂)_(i)NR²²R²³;—(CH₂)_(h)—CO₂R²²; —(CH₂)_(h)NR²²COR²³; —(CH₂)_(h)OCOR²²;—(CH₂)_(h)OCONR²²R²³; —(CH₂)_(h)NR²²COOR²³; —(CH₂)_(h)COR²²;—(CH₂)_(h)SO₂NR²²R²³; —(CH₂)_(h)NR²²SO₂R²³; —SO₂R²²; —(CH₂)_(h)NR²²R²³;—(CH₂)_(h)NR²²CONR²²R²³; or -(CH²)_(h)CONR²²SO₂R²³; R²² and R²³ areindependently selected from hydrogen; C₁₋₆alkyl optionally substitutedby up to three hydroxy groups; trihalomethyl; benzyl; —(CH₂)_(j)COH;—(CH₂)_(j)NR²⁴R²⁵; or a phenyl optionally substituted by up to threegroups selected from C₁₋₆alkyl or C₁₋₆alkoxy; R²⁴ and R²⁵ areindependently selected from hydrogen or C₁₋₄alkyl; Group A is selectedfrom halogen, —SO₂NH₂, —SO₂—(4-methyl)piperazinyl, —NR²²COC₁₋₆alkyl or—NR²²SO₂C₁₋₆alkyl; h is selected from 0, 1, 2 or 3; i is selected from0, 1, 2 and 3;and j is selected from 2 or
 3. 11. A compound according toclaim 3 wherein R² is a C₂₋₃alkyl substituted by one OH group.
 12. Acompound according to claim 11 wherein R² is —CH₂CH₂OH or —CH₂CH₂CH₂OH.13. A compound according to claim 1 wherein R³ is —CO—NH—(CH₂)_(q)R⁷.14. A compound according to claim 1 wherein R⁴ is selected fromhydrogen, C₁₋₄alkyl and phenyl.
 15. A compound according to claim 1wherein W is methyl.
 16. A compound according to claim 1 wherein X and Yare each selected independently from hydrogen, chlorine and fluorine.17. A compound according to claim 1 wherein Z is a bond.